Many modern medical procedures require that synthetic medical devices remain in an individual undergoing treatment. Although a large number of polymeric materials are currently employed to prepare various blood-contacting implantable and extracorporeal medical devices, the thrombogenic nature of such materials can cause serious complications in patients, and ultimately functional failure. As a result, systemic anticoagulation regimens are almost always required clinically to reduce the risk of thrombus formation, especially in the case of vascular grafts. Furthermore, atherosclerosis is prevalent in all developed nations and is the leading cause of death and disability in the United States. Deaths due to cardiovascular disease account for 2,400 deaths per day, or 871,517 deaths per year, more than the next five leading causes of death combined. Currently, severe atherosclerotic coronary or peripheral arterial disease is treated with balloon angioplasty and stenting, bypass grafting, or endarterectomy.
However, the durability of these procedures is limited due to the development of neointimal hyperplasia which results from a cascade of events that ultimately leads to aggressive growth of the smooth muscle cells that line the artery wall and encroach on the lumen, causing restenosis or occlusion of the vessel. As evidence of the widespread nature of this problem, seventy-nine million Americans currently have cardiovascular disease and it is estimated that this number will increase significantly due to the growth of the aging population. Furthermore, it is estimated that $432 billion per year is spent in the United States on cardiovascular disease, with a significant portion being attributed to the cost of repeat interventions (Rosamond W. et al., Circulation, 2007, 115: e69-e171).
One promising therapeutic strategy to prevent thrombosis and neointimal hyperplasia has centered on the use of nitric oxide (NO), a molecule normally produced in endothelial cells that serves to protect the vessel wall. NO is a small, diffusible molecule with a very short half-life that is produced from L-arginine by one of three different NO synthase (NOS) enzymes. NO plays an important role as a potent vasodilator, inhibitor of vascular cell proliferation and migration, inhibitor of platelet aggregation, inhibitor of leukocyte chemotaxis, and stimulator of endothelial cell growth (Ahanchi S. et al., Journal of Vascular Surgery, 2007, 45: A64-73). As a result, compounds that spontaneously decompose to release NO are widely investigated for use in the vasculature.
Metal complexes, nitrosothiols, nitrosamines, and diazeniumdiolates are all samples of molecular structures that have been developed as effective NO donors (Wang P. et al., Chem Rev, 2002, 102: 1091-1134). Notably, diazeniumdiolate NO donors are particularly attractive for medical applications because they dissociate spontaneously under physiological conditions (i.e., 37° C., pH 7.4) to yield two moles of NO per mole of NO donor (Hrabie J. et al., Chem Rev, 2002, 102: 1135-1154). Using synthetic polymeric materials that can release or generate NO locally for extended periods may provide the ultimate method to greatly reducing the risk of thrombosis on the surface of many types of biomedical implants that are in contact with blood, as well as prevent the development of neointimal hyperplasia.
To date, diazeniumdiolated polymers such as polyurethane (Jun H. et al., Biomacromolecules, 2005, 6: 838-844), poly(ethylenimine) (Davies K. et al., J Med Chem, 1996, 39:1148-1156), polymethacrylate (Parzuchowski P. et al., J Am Chem Soc, 2002, 124: 12182-12191), poly(vinyl chloride) (Saavedra J. et al., J Org Chem, 1999, 64: 5124-5131), diamino cross-linked polydimethoxysilane (Smith D. et al., Biomaterials, 2002, 23: 1485-1494), dendrimers (Stasko N. et al., J Am Chem Soc, 2006, 128: 8265-8271) have been the most studied class of NO donor agents. However, no diazeniumdiolated aliphatic biodegradable elastomers for generating NO have been prepared.